The long-term objective of this application is the prevention of autoimmune mediated Type 1 diabetes mellitus. Many promising interventions must be tested in a safe and efficient manner to achieve this goal. A well-organized cooperative network of capable institutes will greatly facilitate the prompt completion of multiple clinical trials needed to select from among these potential interventions. The application responds to the RFA proposing the Type 1 Diabetes TrialNet. The specific aims of the first section, TrialNet at Stanford University, are first, to continue and to improve the infrastructure essential to completing the current Diabetes Prevention Trial - Type 1 (DPT-1) protocols; and second, to conduct new multi-center clinical trials directed at the prevention of Type 1 diabetes mellitus (T1DM) by transforming the current DPT-1 center into a TrialNet center. This section reviews our seven-year experience as a DPT-1 national center in the middle of a high population density geographic location. We highlight our plans for extending and improving recruitment and retention activities for the next seven years. These plans include both completing the current DPT-1 protocol and conducting the expected upcoming pilot trials in subjects with new onset T1DM. These pilot trials will guide the selection of appropriate interventions for any future definitive clinical trials for the prevention of T1DM in high-risk subjects. The second section, DNA Vaccination With Insulin B:9-23, articulates our proposed intervention trial to study this novel therapy in subjects with T1DM. Phase 1 safety studies using DNA vaccination have demonstrated no significant adverse events, so that it is now reasonable to consider this innovative approach as a possible therapy for diabetes prevention. We propose to initiate Phase 1 safety studies followed by Phase 2 efficacy studies using DNA vaccination with insulin B:9-23.